Project Summary In children, tumors affecting the brain result in more cancer-related deaths than any other type of tumor. It is thus critical to identify new therapies. Among pediatric patients, one of the most devastating brain tumor types is Diffuse Intrinsic Pontine Gliomas (DIPG). Our understanding of this deadly disease has recently been advanced by important discoveries, including the finding that the majority of DIPG tumors harbor the histone H3K27M mutation. This mutation results in global hypomethylation of H3K27 residues and is the pathological hallmark for this disease. The applicant has discovered that Wnt5a and STAT3 signaling are critically important for proliferation and survival of H3K27M tumors and inhibiting these pathways restores the reduced H3K27 methylation patterns and leads to tumor cell death. This project aims to further understand how STAT3 is critical for H3K27M tumors and validate STAT3 as a drug target in DIPG tumors. A further goal is to develop additional pediatric patient derived high grade glioma xenografts and cell lines. These techniques will be generalizable to other molecular drivers of tumorigenesis in malignant brain tumors. The proposed research is significant because it is expected to vertically advance therapeutic options for treating DIPG tumors. The candidate is an MD/PhD trained neurosurgeon-scientist with advanced clinical training in pediatric brain tumors whose career goal is to advance treatment strategies for malignant brain tumors through basic and translational research. The career development plan and research will be mentored by Dr. Jann Sarkaria, a physician-scientist whose research goals are in alignment with the candidate. This proposal combines the strengths of the candidate, the mentors, and the research institution in order to provide an opportunity for the candidate to become a successful independent neurosurgeon-scientist.